3-benzoylpropionamido cephalosporanic derivatives

ABSTRACT

The antibacterial agents of this invention present the following structural formula: ##SPC1## 
     In which 
     R 1  is --OH, alkoxycarbonyloxy of 2 to 6 carbon atoms, arylsulfonyl of 6 to 10 carbon atoms or thiocyanato; 
     R 2  is --H, halo or phenyl; 
     R 3  is --H, an alkali metal or --NH 4  ; and 
     Y is ##EQU1## wherein R 4  is --H, alkanoyloxy of 2 to 6 carbon atoms, ##EQU2## or WHEN TAKEN WITH THE 3-CARBOXY GROUP, ##SPC2##

DESCRIPTION OF THE INVENTION

In accordance with this invention there is provided antibacterial agentsof the formula: ##SPC3##

In which

R¹ is --OH, alkoxycarbonyloxy of 2 to 6 carbon atoms, arylsulfonyl of 6to 10 carbon atoms or thiocyanato;

R² is --H, halo or phenyl;

R³ is --H, an alkali metal or --NH₄ ; and

Y is ##EQU3## wherein R⁴ is --H, alkanoyloxy of 2 to 6 carbon atoms,##EQU4## or when taken with the 3-carboxy group ##SPC4##

The compounds of this invention are prepared by coupling techniques wellknown to the chemical arts. Thus, dehydrative coupling or mixedanhydride coupling as applied in the area of peptide synthesis areespecially useful methods for the coupling reactions involved in theformation of the amides of 7-aminocephalosporanic acid derivatives and6-amino penicillanic acid derivatives. In addition, the carboxylic acidinitial reactants may, if desired, be converted to the correspondingacid halide by conventional means for use as the desired acylatingagent.

The 3-disubstituted propionic acid reactants presenting the structuralformula: ##SPC5##

In which the

Groups R¹ and R² are defined above, are either known compounds (U.S.3,714,218 and U.S. 3,749,750) or are prepared by techniques known to thechemist. For example, 3-(p-chlorobenzoyl)-3-hydroxy-propionic acid isprepared by reacting 3-bromo-3-(p-chlorobenzoyl)propionic acid withaqueous 10 percent sodium carbonate. The same displacement reactionyields 3-(4-biphenylylcarbonyl)-3-hydroxypropionic acid from the3-bromoprecursor.

The preferred group of compounds, from the standpoint of availability ofthe reactants, ease of reaction and production economics, are those ofthe formula: ##SPC6##

In which

R¹ is --OH, iso-butoxycarbonyloxy, tolylsulfonyl or thiocyanato;

R² is --Cl or phenyl; and

Y is ##EQU5## wherein R⁴ is --H or acetoxy.

The compounds of this invention have been found to be activeantibacterials effective against gram-positive and gram-negative testorganisms as well as penicillin resistant staphlococcus, by using thewell known and scientifically accepted agar serial dilution testingtechnique. Thus, the compounds of this invention are useful in thefields of comparative pharmacology and in microbiology and may be usedfor the treatment of bacterial infections amenable to treatment withpenicillin and infestations antibiotics. occurred.

The following examples illustrate the preparation of representativepenicillin and cephalosporin derivatives. The activity of each productof the examples is presented for those specific bacterial strainsagainst which the compound exemplified was active at or below 250micrograms per milliliter. The representative nature of the bacterialstrains employed to demonstrate antibacterial activity are indicative ofthe broader applicability of the compounds of this invention in thecontrol of bacterial infectations other than those specifically referredto in each of the following examples. The bacterium are named followedby the specific strain and the concentration in micrograms permilliliter at which 100 percent inhibition occured. The abbreviationsfor each bacterium are:

    BA SU       Bacillus subtilis                                                 BO BR       Bordetella bronchiseptica                                         ES CO       Escherichia coli                                                  HE SP       Herellea species                                                  KL PN       Klebsiella penumoniae                                             NE CA       Neisseria catarrhalis                                             PR VU       Proteus vulgaris                                                  SA PA       Salmonella paratyphi                                              ST AU       Staphylococcus aureus                                         

EXAMPLE I 7-[3-(p-Chlorobenzoyl)-3-hydroxypropionamido]cephalosporanicacid isobutyl carbonate.

To a tetrahydrofuran solution of 1.14 grams (5 millimole) of3-(p-chlorobenzoyl)-3-hydroxypropionic acid in a salt-ice bath was addedtriethyl amine (10 millimole) followed by isobutyl chloroformate. Afterthe solution was stirred for 15 minutes a cold solution of 1.36 grams (5millimole) of 7-aminocephalosporanic acid and 0.50 gram triethylamine ina mixture of 20 milliliter tetrahydrofuran and 10 milliliters H₂ O wasslowly added. Some insoluble material was filtered off. The solvent wasremoved at reduced pressure around 30°C. The residue was dissolved in 50milliliters H₂ O and a small amount of insoluble material was filtered.Acidification of the aqueous solution 6N hydrochloric acid caused asolid to precipitate which was collected and washed with water. An ethylacetate solution of the crude solid was dried over anhydrous MgSO₄.After the solvent was removed the solid residue was treated with pentaneand collected to give 2.0 grams polymorphous product.

Elemental Analysis for C₂₅ H₂₇ ClN₂ O₁₀ S: Calc'd: C, 51.50; H, 4.67; N,4.81. Found: C, 52.10; H, 4.70; N, 4.63.

    ______________________________________                                        BA SU       6633          1.95                                                HE SP       9955          250                                                 KL PN       10031         125                                                 NE CA       8193          250                                                 PR VU       6896          125                                                 SA PA       11737         250                                                 ST AU        6538P        1.95                                                ST AU       SMITH         1.95                                                ST AU       CHP           7.81                                                ST AU       53-180        3.90                                                ______________________________________                                    

EXAMPLE II6-[3-(p-Chlorobenzoyl)-3-(p-tolylsulfonyl)propionamido]penicillanicacid.

The titled compound was obtained by following the procedure of Example1, in which equimolar quantities of 6-amino penicillanic acid, and3-(p-chlorobenzoylyl)-3-(p-tolysulfonyl)propionic acid were utilized.

Elemental Analysis for C₂₅ H₂₅ ClN₂ O₇ S.sub. 2 .1/2H₂ O: Calc'd: C,52.30; H, 4.57; N, 4.88. Found: C, 52.36; H, 4.52; N, 4.35.

    ______________________________________                                        BA SU       6633          3.90                                                HE SP       9955          125                                                 KL PN       10031         250                                                 NE CA       8193          7.81                                                PR VU       6896          250                                                 ST AU        6538P        .976                                                ST AU       SMITH         .976                                                ST AU       CHP           31.3                                                ST AU       53-180        125                                                 ______________________________________                                    

EXAMPLE III7-[3-(p-chlorobenzoyl)-3-(p-tolylsulfonyl)propionamino]cephalosporanicacid.

The titled compound was obtained by following the procedure of Example Iin which an equimolar quantity of3-(p-chlorobenzoyl)-3-(p-tolylsulfonyl)propionic acid was employed.

Elemental Analysis for C₂₇ H₂₅ ClN₂ O₉ S₂ : Calc'd: C, 52.50; H, 4.06;N, 4.51. Found: C, 52.11; H, 4.05; N, 3.90.

    ______________________________________                                        BA SU       6633          .976                                                KL PN       10031         62.5                                                NE CA       8193          250                                                 PR VU       6896          125                                                 SA PA       11737         125                                                 ST AU        6538P        1.95                                                ST AU       SMITH         1.95                                                ST AU       CHP           3.90                                                ST AU       53-180        3.90                                                ______________________________________                                    

EXAMPLE IV7-[3-(p-Chlorobenzoyl)-3-)p-tolylsulfonyl)propionamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

The titled compound was obtained by following the procedure of Example Iin which equimolar quantities of3-(p-chlorobenzoyl)-3-(p-tolylsulfonyl)propionic acid and7-aminodesacetoxycephalosporanic acid were utilized.

Elemental Analysis for C₂₅ H₂₃ ClN₂ O₇ S.sub. 2 : Calc'd: C, 53.33; H,4.12; N, 4.97. Found: C, 53.06; H, 4.16; N, 4.50.

    ______________________________________                                        BA SU       6633          15.6                                                ST AU       6538P         15.6                                                ST AU       SMITH         15.6                                                ST AU       CHP           62.5                                                ST AU       53-180        31.3                                                ______________________________________                                    

EXAMPLE V7-[3-(p-Chlorobenzoyl)-3-hydroxypropionamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

The title compound was obtained by following the procedure of Example I,in which an equimolar quantity of 7-aminodesacetoxycephalosporanic acidwas utilized

Elemental Analysis for C₁₈ H.sub. 17 ClN₂ O₆ S: Calc'd: C, 50.86; H,4.03; N, 6.60. Found: C, 51.93; H, 4.12; N, 6.34.

    ______________________________________                                        BA SU       6633          31.3                                                HE SP       9955          125                                                 PR VU       4617          125                                                 ST AU        6538P        15.6                                                ST AU       SMITH         15.6                                                ST AU       CHP           31.3                                                ST AU       53-180        31.3                                                ______________________________________                                    

EXAMPLE VI6-[3-(4-Biphenylylcarbonyl)-3-hydroxypropionamido]penicillanic acid.

The title compound was prepared by following the procedure of Example Iin which equimolar quantities of3-(4-biphenylylcarbonyl)-3-hydroxypropionic acid and 6-aminopenicillanicacid were utilized.

Elemental Analysis for C₂₄ H₂₄ N.sub. 2 O₆ S: Calc'd: C, 61.53; H, 5.16;N, 5.98. Found: C, 61.74; H, 5.40; N, 6.22.

    ______________________________________                                        BA SU       6633          1.95                                                HE SP       9955          62.5                                                NE CA       8193          7.81                                                ST AU        6538P        .244                                                ST AU       SMITH         .244                                                ST AU       CHP           15.6                                                ST AU       53-180        31.3                                                ______________________________________                                    

EXAMPLE VII6-[3-(p-Chlorobenzoyl)-3-thiocyanatopropionamido]penicillanic acidpotassium salt.

3-(p-Chlorobenzoyl)-3-thiocyanatopropionic acid (1.40 grams, 5millimole) was dissolved in 5 milliliter dimethylformamide. Carbonyldiimidazole (0.82 gram, 5 millimole) was added in one portion. Themixture was stirred under nitrogen for 1/2 hour and evacuated for 1/2hour. To the above solution, chilled in an ice bath, was added a coldsolution of 1.08 grams (5 millimole) 6-aminopenicillanic acid and 1.00gram (10 millimole) of triethylamine in methylene chloride. The reactionmixture was stirred, in the ice bath for 2 hours, filtered, andconcentrated in vacuo at 30°C. To the residue dissolved in methylenechloride was added a solution of 1 milliliter of a 2 Molar potassiumsalt of 2-ethyl hexanoate in propanol. Addition of anhydrous ethercaused precipitation of the potassium salt, which was collected, washedwith ether, and dried.

Elemental Analysis for C₁₉ H₁₇ ClN₃ O₅ S₂ K.H₂ O: Calc'd: C, 43.55; H,3.66; N, 8.02. Found: C, 43.85; H, 3.48; N, 8.63.

    ______________________________________                                        BA SU       6633          62.5                                                HE SP       9955          250                                                 NE CA       8193          250                                                 ST AU        6538P        15.6                                                ST AU       SMITH         15.6                                                ST AU       CHP           125                                                 ST AU       53-180        125                                                 ______________________________________                                    

EXAMPLE VIII7-[3-(p-Chlorobenzoyl)-3-thiocyanatopropionamido]cephalosporanic acid,potassium salt.

The title compound was prepared by following the procedure of Example 7in which 7-aminocephalosporanic acid was utilized.

Elemental Analysis for C₂₁ H₁₇ ClN₃ O₇ S₂ K.1/4(C₂ H₅)₂ O.11/2 H₂ O:Calc'd: C, 42.94; H, 3.69; N, 6.99. Found: C, 42.11; H, 3.02; N, 6.38.

    ______________________________________                                        BA SU       6633          1.95                                                BO BR       4617          250                                                 ES CO       9637          250                                                 KL PN       10031         62.5                                                NE CA       8193          250                                                 PR VU       6896          250                                                 SA PA       11737         125                                                 ST AU        6538P        3.90                                                ST AU       SMITH         3.90                                                ST AU       CHP           15.6                                                ST AU       53-180        15.6                                                ______________________________________                                    

EXAMPLE IX7-[3-(4-Biphenylylcarbonyl)-3-hydroxypropionamido]cephalosporanic acid.

The title compound was prepared by following the procedure of Example 1,in which 3-(4-biphenylylcarbonyl)-3-hydroxypropionic acid was utilized.

Elemental Analysis for C₂₆ H₂₄ N₂ O₈ S: Calc'd: C, 59.55; H, 4.61; N,5.34. Found: C, 59.64; H, 4.53; N, 5.26.

    ______________________________________                                        BA SU       6633          3.90                                                HE SP       9955          250                                                 KL PN       10031         250                                                 NE CA       8193          250                                                 SA PA       11737         250                                                 ST AU        6538P        1.95                                                ST AU       SMITH         1.95                                                ST AU       CHP           3.90                                                ST AU       53-180        3.90                                                ______________________________________                                    

EXAMPLE X7-[3-(4-Biphenylylcarbonyl)-3-thiocyanatopropionamido]cephalosporanicacid, potassium salt.

The title compound was prepared by following the procedure of Example 7,in which 3-(4-biphenylcarbonyl)-3-thiocyanatopropionic acid and7-aminocephalosporanic acid were utilized.

Elemental Analysis for C₂₇ H.sub. 22 N₃ O₇ S₂ K: Calc'd: C, 53.71; H,3.68; H, 6.96. Found: C, 53.53; H, 3.53; N, 6.74.

    ______________________________________                                        BA SU       6633          3.90                                                ES CO       9637          250                                                 KL PN       10031         62.5                                                NE CA       8193          250                                                 PR VU       6896          125                                                 SA PA       11737         125                                                 ST AU        6538P        3.90                                                ST AU       SMITH         3.90                                                ST AU       CHP           31.3                                                ST AU       53-180        15.6                                                ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##SPC7##in which R¹ is--OH, alkoxycarbonyloxy of 2 to 6 carbon atoms, arylsulfonyl of 6 to 10carbon atoms or thiocyanato; R² is --H, halo or phenyl; R³ is --H, analkali metal or -NH₄, and R ⁴ is --H, alkanoyloxy of 2 to 6 carbonatoms, or when taken with the 3-carboxy group, ##SPC8##
 2. The compoundof claim 1 which is7-[3-(p-chlorobenzoyl)3-hydroxypropionamido]cephalosoporanic acidisobutyl carbonate.
 3. The compound of claim 1 which is7-[3-(p-chlorobenzoyl)3-(p-tolylsulfonyl)propionamido]cephalosporanicacid.
 4. The compound of claim 1 which is7-[3-(p-chlorobenzoyl)3-(p-tolylsulfonyl)-propionamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.
 5. The compound of claim 1 which is7-[3-(p-chlorobenzoyl)3-hydroxypropionamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.
 6. The compound of claim 1 which is7-[3-(p-chlorobenzoyl)3-thiocyanatopropionamido]cephalosporanic acid. 7.The compound of claim 1 which is7-[3-(4-biphenylylcarbonyl)-3-hydroxypropionamido]cephalosporanic acid.8. The compound of claim 1 which is7-[3-(4-biphenylylcarbonyl)-3-thiocyanatopropionamido]cephalosporanicacid.
 9. A compound of claim 1 of the formula: ##SPC9##in which R¹ is--OH, iso-butoxycarbonyloxy, tolylsulfonyl or thiocyanato; R² is --Cl orphenyl; and R⁴ is --H or acetoxy;